PROJECT 4: SUMMARY/ABSTRACT Although reactive electrophiles are important contributors to states of human health and disease, these molecules are generally overlooked in exposomic investigations. For example, many electrophiles are inherently toxic and carcinogenic because they modify human DNA and proteins, but are too reactive to be measured in blood. One approach for investigating exposures to reactive electrophiles involves measurement of adducts formed from reactions with blood proteins. Human serum albumin (HSA) contains a nucleophilic hotspot (Cys34), which is the major scavenger of reactive oxygen species and other electrophiles that enter the blood from inhalation, ingestion and metabolism. Our laboratory has developed an untargeted assay (`adductomics') for profiling HSA-Cys34 adducts and has compiled a library of over a hundred such adducts detected in human blood. Interestingly, some adducts are specific to particular exposures (e.g., benzene oxide from benzene) while others relate more generally to oxidative stress and dysregulation of metabolic pathways (e.g. Cys34 oxidation products and disulfides of circulating thiols). We hypothesize that this combination of chemical-specific and oxidative-stress adducts in blood establishes patterns or `signatures' of adducts that can be related to subjects' exposures to Superfund contaminants and their interactions with environmental stressors. By profiling HSA adducts in blood from cross sectional studies of populations heavily exposed to three Superfund chemicals (benzene, PAHs & arsenic), we propose to find their adductomic signatures. Then, by targeting these adductomic signatures in archived serum from a large cohort study being conducted by the National Cancer Institute in Shanghai, China, we will investigate contributions of benzene exposure on risks of lymphoid and myeloid cancers and of PAH and arsenic exposures on risks of lung cancer. Project 4 will directly address Problems 3 & 4 on mixtures/complexity by examining a plethora of adducts associated with exposures to Superfund chemicals and environmental stressors. Since Project 4 will explore the use of adductomic signatures as biomarkers of past exposure in prospective studies of cancers, it also directly addresses Problem 2. Project 4 will provide insights to Project 3 regarding protein modifications and bioactivation pathways, to Project 1 regarding mechanisms by which arsenic causes cancer in humans, either alone or in conjunction with psycho-social stress and obesity, and to Projects 2 and 5 regarding contributions of reactive intermediates to toxicity and degradation.